For sometime it has been known that it is possible to administer drugs to a patient by transdermal drug delivery systems. Essentially, the methodology involves placing the drug on the surface of the skin and/or mucous membrane and allowing the drug to permeate through the skin into the patient's blood supply for systemic relief and/or to the specific location where relief is required in order to obtain a local effect. Transdermal drug delivery works well for some drugs and not so well for others which are not readily absorbed through the skin. When a drug is not readily absorbed through the skin, other methodologies and/or compounds can be used in order to enhance the rate of absorption, i.e., get more drug through the skin in a given unit of time.
One well-known method of enhancing the rate of drug delivery is to add an additional component which acts as an absorption promoter, i.e., a compound which enhances the rate of transdermal drug permeation through the skin. Different permeation enhancers operate by different mechanisms. Further, drugs which do not absorb well through the skin are hindered for different reasons. Accordingly, not all permeation enhancers will enhance the permeation of all drugs. The permeation enhancer must be characterized by assisting in overcoming a difficulty which causes the particular drug not to be absorbed well. One drug which is known not to be absorbed well through the skin is molsidomine.
Molsidomine (N-5-ethoxycarbonyl-3-morpholinosydnonimine) is a novel sydnonimine derivative with a mesoionic aromatic ring. It is also an ester prodrug. ##STR1## Molsidomine is a white colorless crystal powder, practically tasteless or odorless. The imine has a molecular weight of 242 with a melting point of 140.degree.-141.degree. C. and a pK.sub.a value of 3.34 at 25.degree. C. Its maximum UV absorption wavelength is 326 nm in CHCl.sub.3. The solubilities of molsidomine in various solvent systems are shown in Table I.
TABLE I ______________________________________ Saturated Solubilities of Molsidomine in Various Vehicles Vehicles Solubilities at 25.degree. C. (%) ______________________________________ 1 Glycol salicylate 15.1 2 Propylene glycol 6.37 3 PEG 400 5.23 4 Glycerin 1.80 5 Oleic Acid 1.37 6 Octyl.decyl oil 0.36 7 Isopropyl myristate 0.09 ______________________________________
Reference: Yamada et al., Chem. Pharm. Bull., 35, 3399-3406 (1987).
Freely soluble in CHCl.sub.3 PA0 Soluble in dil HCl, ethanol, ethyl acetate and methanol PA0 springly soluble in water, acetone, benzene PA0 very slightly soluble in ether, petr ether
Reference: Merck Index, 10.sup.th edition, page 892 (1983)
It is soluble in propylene glycol and a variety of organic solvents. The chemical stability of molsidomine has been investigated in detail by Asahi et al. (1971). It is most stable in aqueous solution of pH 5 to 7 (Table II), but is photosensitive, particularly in sunlight.
TABLE II ______________________________________ Chemical Stability of Molsidomine pH t.sub.90 (days) at 20.degree. C. ______________________________________ 1-2 38 4 250 5-7 950 (2.6 years) 10 400 11 40 ______________________________________
Reference: Yutaka Asahi, K. Shinozaki, and M. Nagaoka, Chemical & Pharmaceutical Bulletin, Vol 19, 1079-1088 (1971)
Molsidomine has been shown to possess a sustained anti-antinal effect and can be metabolized to SIN-1, which is readily converted into the active metabolite SIN-1A (carries a free nitroso group), Scheme 1. ##STR2##
A very recent investigation on the vasodilation action of molsidomine and other vasodilators, including nitroglycerine reveals that it is the nitric oxide, liberated from the active metabolite SIN-1A, that activates the soluble guanylate cyclase, which in turn causes vasodilation. This is a major difference from the vasodilation action of nitroglycerin.
The coronary vasodilation action of nitroglycerin depends on the presence of cysteine. Cysteine deficiency was found to be associated with tolerance developed for nitroglycerin uses. After prolonged exposure to nitroglycerin, tolerance toward the drug developed in coronary strips can be antagonized by cysteine. However, the active metabolite of molsidomine, SIN-1A, is active in both the presence and absence of cysteine; therefore, molsidomine produces insignificant tolerance (Kulovetz and Holzmann, 1985) making it a better alternative for anti-anginal therapy.
Transdermal delivery of molsidomine has been studied and it has been shown that in an in vivo rat experiment a combination of propylene glycol with 10% oleic acid produced an estimated flux of 399 .mu.g/hr-cm.sup.2 for molsidomine.
It has also been shown that a single oral dose of 2 mg of molsidomine can produce anti-anginal effects in patients with coronary heart disease for 3 to 5 hours. Different oral dosing levels can benefit patients with different degrees of coronary heart disease. Typically, it is suggested that oral doses of 2 mg three times daily, or 4 mg four times daily should be given. Pharmacokinetic data indicate that the total clearance and peak plasma concentration of molsidomine were 46,000 ml/hr and 15 mg/ml, respectively, following the administration of an oral dose of 2 mg. The bioavailability of molsidomine from oral doses is 44%. Generally, the effective blood concentration of a drug is less than the peak plasma concentration; therefore, an estimation of target flux based on the effective blood concentration should be a better indication of the delivery rate required to produce therapeutic response.
European patent application 0,127,468, entitled "Percutaneous Pharmaceutical Preparation for External Use," was published Dec. 6, 1984. The application discloses pharmaceutical percutaneous formulations containing various amounts of molsidomine and various absorption promoters.